Oxobisbenzoxazin-2-ones and process for their production



United States Patent 3,401,167 OXOBISBENZOXAZIN-Z-ONES AND PROCESS FOR THEIR PRODUCTION John Shave], Jr., Mendham, and George Bobowski, Morristown, N.J., assignors to Warncr Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Filed Jan. 7, 1966, Ser. No. 519,197 7 Claims. (Cl. 260-246) ABSTRACT OF THE DISCLOSURE The present invention describes certain oxobisbenzoxazin-Z-ones of the formula:

wherein R is lower alkyl, lower alkenyl or cycloalkyl, R and R may be hydrogen, halogen, lower alkoxy or carbamoyloxy. These compounds are useful as anti-inflammatory agents.

This invention relates to compositions of matter. More particularly, this invention relates to oxobisbenzoxazin- 2-ones of the formula:

R Rs 6' L wherein R may be straight or branched chain lower alkyl of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like; lower alkenyl such as allyl, methylallyl, dimethylallyl; cycloalkyl of 3 to 8 carbon atoms such as cyclopropyl, cyclopropylrnethyl, cyclopentyl, cyclohexyl and the like; R and R may be hydrogen, halogen such as chlorine, bromine, iodine and fluorine; straight or branched chain lower alkoxy of 1 to 6 carbon aoms such as methoxy, ethoxy, propoxy, isopr-opoxy, butoxy, isobutoxy and the like; lower alkyls of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like; carbamoyloxy such as in which R, has the same significance as R and may also be a nitro group.

The symbols R R R and R, as used hereinafter have the same meaning as defined above.

The compounds of this invention are useful as antiinflammatory agents. For example, in a test for determination of anti-inflammatory activity in warm-blooded mammals such as mice employing a procedure described by ODriscoll et al., Canadian Journal of Physiology and Pharmacology, Volume 42 (1964), it was found that some of the compounds are capable of suppressing lung inflammation in albino mice to a marked degree and in some instances to an extent estimated to be up to 55.2% over that observed in untreated mice. Accordingly, these compounds are useful in treating the inflammatory process either systemically or localy. In use, the compounds of this invention are combined with an inert pharmaceutical diluent to form dosage forms such as tablets, capsules, elixirs, suspensions, suppositories, parenterals and the like With the active ingredient being present in an amount from 1 mg. to 1000 mg. per dosage unit. The compounds of this invention may also be combined with other known thereapeutic agents, for example, steroids such as ,6- methasone, B-methasone-l7-valerate, prednisolone, cortisone and the like, analgesics such as aspirin, tranquilizers such as the 1,4-benz0diazepines, antibiotics such as neomycin and colistin, antihistamines such as chlorpheniramine and the like to enhance and broaden their therapeutic spectrum.

According to this invention the above compounds may be prepared by two procedures. The first procedure, a one-step process which is hereinafter referred to as method A, comprises refluxing ortho-hydroxy aromatic aldehydes with any aryl or any alkyl isocyanate in a solvent such as benzene or tatrahydrofuran. The reactants are preferably employed at a ratio of about 1 mole of the aldehyde to about 2 mole of the isocyanate. The reaction product thus obtained is recovered upon removal of the solvent. Exemplary of the aromatic aldehydes which may be conveniently employed in this reaction are salicylaldehyde, S-chloro-salicylaldehyde, .S-methoxysalicylaldehyde and the like. Exemplary of the isocyanates which may be employed in this reaction are phenylisocyanate, Inethylisocyanate, ethylisocyanate and the like.

The second method, a two-step process which is hereinafter identified as method B, comprises the self-condensation of a compound of the Formula II:

in the presence of an acid catalyst with a provision for the azeotropic removal of water. This procedure is fully described in copending application Ser. No. 504,142 tiled Oct. 23, 1965.

The following examples are included in order further to illustrate the invention. All temperatures are given in degrees Centigrade.

EXAMPLE 1 o N-CnH 4,4'-oxobis(3,4-dihydro-3-phenyl-2H-benzoxazin-Z-one) A solution of 12.2 g. of salicylaldehyde, 11.9 g. of phenyl isocyanate, and 3 drops of pyridine in 20 ml. of anhydrous tetrahydrofuran is refluxed for one hour and then allowed to stand at 20 to 30 C. for five days. The solid is filtered off and Washed with tetrahydrofuran to give 3.9 g. of nearly white crystals, M.P. 2l2-213 C. Concentration of the mother liquor and cooling gives 8.4 g. of 4,4 oxobis(3,4 dihydro 3 phenyl 2. H benzoxazin- 2-one) as yellowish colored crystals, M.P. 203-208 C.

. a Two recrystallizations of the first crop from tetrahydrofuran-dimethylformamide gives analytically pure, white, shiny needles, M.P. 241-242 C., decomp.;

Nuiul mux.

ADMSO max.

EXAMPLE 2 N-C1I3 4,4-oxobis(3,4-dihydro-3-methyl-2H-1,3-benzoxazin- 2-one) Method A.-To a stirred solution of 24.4 g. of salicylaldehyde and 0.2 ml. of triethylamine in 25 ml. of dry benzene is added a solution of 30.8 g. of methyl isocyanate in 25 ml. of benzene over a period of 30 minutes. The exothermic reaction takes place immediately, causing the solution to reflux and white crystals to begin to separate. After the reaction mixture is cooled to 20 to 30 C. and allowed to stand for about 10 to 18 hours, 12.2 g. of 4,4-oxobis 3,4-dihydro-3-methy1-2H-1 ,3 -benzoxazin-2- one) as white crystals is filtered 01f, M.P. 204-206 C., decomp. Recrystallization from benzene gives analytically pure white crystals, M.P. 210211 C., decomp.;

Nuiol A212? mu (6) 266.5 (2,370), 273.5 (2,200); u 946 (s), 962, (s), 1238 (s), 1 10? (ms), 1498 (m), 1602 (m), 1720 (wide band, vs) emf; 9 ,19 912 (m),

978 (s), 1235-1190 (wide band, 5), 1402 (ms), 1442 (s), 1467 (vs), 1496 (m), 1603 (m), 17451722 (wide band, vs), 2950 (w) cmf Analysis for C H N O .Calc.: C, 63.52; H, 4.74; N, 8.23. Found: C, 63.71; H, 4.89; N, 8.29.

Method B.A solution of 3.0 g. of 3,4-dihydro-4-hydroxy-3-methyl-2H-1,3-benzoxazin-2-one and 0.01 g. of p-toluenesulfonic acid monohydrate in 60 ml. of anhydrous benzene is refluxed for two hours, and 0.15 ml. of water separated in a Dean-Stark trap. Concentration of the solution to about 30 ml. and cooling gives 1.7 g. of 4,4 oxobis(3,4 dihydro 3 methyl 2H benzoxazin- 2-one), as white crystals which melt at 207-209 C., decomp. Recrystallization from benzene gives pure 4,4- oxobis (3 ,4-dihydro-3-methyl-2H-benzoxazin-2-one) M.P. 210211 C., decomp. The spectral data are identical with the product obtained by Method A and a mixed melting point is not depressed.

EXAMPLE 3 0 NC2II5 4,4-oxobis(3,4-dihydro-3-ethyl-2H-benzoxazin-Z-one) A solution of 6.1 g. of salicylaldehyde, 7.1 g. of ethyl isocyanate, and 5 drops of triethylamine in 50 ml. of anhydrous ether is refluxed for one hour and then allowed to stand at room temperature for four days. The solvent is removed in vacuo at 30 and the residue is refluxed with 50 ml. of isopropyl ether for one hour. Upon standing at room temperature 5.8 g. of white crystals are collected,

, (MIL-1;

. .4 M.P. 158162. Recrystallization from isopropanol gives 3.9 g. of analytically pure 4,4-oxobis-(3,4-dihydro-3- ethyl--2H-benzoxazin-2-one), M.P. 163164;

7213? 2675 273 75331? 750 942 (s), 1194 (S), 1211 (s), 1228 (S), 1423 (s), 1722 (Vs) 7,9 5,9 975-940 (wide band, s)

1190 (s), 1227 (s), 1423 (s), 1467 (vs), 1742-1756 (wide band, vs), 2980 (m) cm.-

Analysis for C H N O .Calc.: C, 65.21; H, 5.47; N, 7.61. Found: C, 65.51; H, 5.62; N, 7.62.

EXAMPLE 4 4,4-oxobis 3,4-dihydro-3-cycl0hexyl-2H-benzoxazin- 2-one) A solution of 6.1 g. of salicylaldehyde, 9.4 g. of cyclohexylisocyanate and 5 drops of triethylamine in ml. of dry benzene is refluxed for one hour. After the solution is allowed to stand at 20 to 30 C. for two days, 7.3 g. of white crystals are collected, M.P. 224227 C., decomp. Two recrystallizations from ethyl acetate gives analytically pure white crystals of 4,4-oxobis(3,4'-dihydro-3-cyclo hexyl-2H-benzoxazin-2-one), M.P. 235236 C., decomp;

III/1(6) 266 (2400), 273 (2250); 11,2131? 760 (ms) L wk wherein R is a member of the group consisting of lower alkyl, lower alkenyl, phenyl and cycloalkyl of 3 to 8 carbon atoms, and R and R are each a member of the group consisting of hydrogen, halogen, lower alkoxy,

lower alkyl and nitro.

2. 4,4'-oxobis(3,4-dihydro-3-phenyl-2H-l,3-benzoxazin- 2-one).

3. 4,4 oxobis(3,4-dihydro-3-methyl-2H-1,3-benzoxazin-2-one).

4. 4,4 oxobis(3,4-dihydro-3-ethyl-2H-1,3-benzoxazin- 2-one).

5. 4,4 oxobis(3,4-dihydro-3-cyclohexyl-2H-1,3-benzoxazin-Z-one) 6. Process for the production of a compound of the formula:

NRr

wherein R is a member of the group consisting of lower alkyl, lower alkenyl, phenyl and cycloalkyl of 3 to8 5 6 carbon atoms, and R and R are each a member of the in a solvent system selected from the group consisting of group consisting of hydrogen, halogen, lower alkoxy, benzene and tetrahydrofuran. lower alkyl and nitro, which comprises refluxing a mem- 7. A process according to claim 6 wherein said isober selected from the group consisting of phenyl, lower cyanate is employed at about 2 mols to about 1 mol of alkyl, lower alkenyl and cycloalkyl of 3 to 8 carbon 5 said ortho-hydroxy aromatic aldehyde. atoms isocyanate with ortho-hydroxy aromatic aldehyde References Cited of the formula Strube et al.: Rec. Trav. Chim. IPays-Bas vol. 83, pages 1191-8 (1964), Qdi. R3.

10 HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

CHO 

